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A CASQ1 founder mutation in three Italian families with protein aggregate myopathy and hyperCKaemia
  1. Claudia Di Blasi1,
  2. Serena Sansanelli1,
  3. Alessandra Ruggieri1,
  4. Manuela Moriggi2,
  5. Michele Vasso2,3,
  6. Adamo Pio D'Adamo4,
  7. Flavia Blasevich1,
  8. Simona Zanotti1,
  9. Cecilia Paolini5,
  10. Feliciano Protasi5,
  11. Frediano Tezzon6,
  12. Cecilia Gelfi2,3,
  13. Lucia Morandi1,
  14. Mauro Pessia7,
  15. Marina Mora1
  1. 1Neuromuscular Diseases and Neuroimmunology Unit, Foundation IRCCS Neurological Institute C. Besta, Milano, Italy
  2. 2Department of Biomedical Sciences for Health, University of Milano, Milano, Italy
  3. 3 CNR-Institute of Bioimaging and Molecular Physiology, Milano, Italy
  4. 4Medical Genetics, University of Trieste, Trieste, Italy
  5. 5CeSI, Center for Research on Ageing & Department of Neuroscience, Imaging, and Clinical Sciences, University G D'Annunzio of Chieti, Chieti, Italy
  6. 6Neurology Unit, F Tappeiner Hospital of Merano, Merano, Italy
  7. 7Faculty of Medicine, Section of Physiology and Biochemistry, Department of Experimental Medicine, University of Perugia, Perugia, Italy
  1. Correspondence to Dr Marina Mora, Muscle Cell Biology Lab, Neuromuscular Diseases and Neuroimmunology Unit, Neurological Institute ‘C Besta’, Via Temolo 4, Milano 20126, Italy; mmora{at} and Dr Claudia Di Blasi, Neuromuscular Diseases and Neuroimmunology Unit, Foundation IRCCS, Neurological Institute C Besta, Milano, Italy;


Background Protein aggregate myopathies are increasingly recognised conditions characterised by a surplus of endogenous proteins. The molecular and mutational background for many protein aggregate myopathies has been clarified with the discovery of several underlying mutations. Familial idiopathic hyperCKaemia is a benign genetically heterogeneous condition with autosomal dominant features in a high proportion of cases.

Methods In 10 patients from three Italian families with autosomal dominant benign vacuolar myopathy and hyperCKaemia, we performed linkage analysis and exome sequencing as well as morphological and biochemical investigations.

Results and conclusions We show, by Sanger and exome sequencing, that the protein aggregate myopathy with benign evolution and muscle inclusions composed of excess CASQ1, affecting three Italian families, is due to the D244G heterozygous missense mutation in the CASQ1 gene. Investigation of microsatellite markers revealed a common haplotype in the three families indicating consanguinity and a founder effect. Results from immunocytochemistry, electron microscopy, biochemistry and transfected cell line investigations contribute to our understanding of pathogenetic mechanisms underlining this defect. The mutation is common to other Italian patients and is likely to share a founder effect with them. HyperCKaemia in the CASQ1-related myopathy is common and sometimes the sole overt manifestation. It is likely that CASQ1 mutations may remain undiagnosed if a muscle biopsy is not performed, and the condition could be more common than supposed.

  • Molecular genetics
  • Neuromuscular disease
  • Clinical genetics
  • Genome-wide

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